Method of treatment with compounds having retinoid-like activity and reduced skin toxicity and lacking teratogenic effects

ABSTRACT

Compounds that provide non-teratogenic effects and lack irritation to the skin are shown in the formula below where the partially drawn ring signifies an aromatic ring which may be carbocyclic or heteroaromatic, 6-membered or 5-membered, and may be condensed with another ring. R 1  is lower alkyl, Cl, Br, or I, R 2  is H, lower alkyl, Cl, Br, or I, and R 3  is lower alkyl, Cl, Br, I, or is an ether, thioether, ester, thioester, amine or substituted amine group. ##STR1##

FIELD OF THE INVENTION

The present invention is directed to methods of administering to mammalsincluding humans, compounds which have retinoid like activity and whichlack substantial teratogenic activity and have substantially reducedskin toxicity. The present invention is also directed to pharmaceuticalcompositions adapted for administering said compounds having retinoidlike activity, reduced skin toxicity, and lacking substantialteratogenic activity. In some instances the present invention is alsodirected to novel compounds having said retinoid like activity, reducedskin toxicity, and lacking teratogenic activity.

BRIEF DESCRIPTION OF THE PRIOR ART

Compounds which have retinoid like activity are well known in the art,and are described in numerous United States and foreign patents and inscientific publications. It is generally known and accepted in the artthat retinoid like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating dermatoses,such as acne, Darier's disease, psoriasis, icthyosis, eczema and atopicdermatitis, and for treating and preventing malignant hyperproliferativediseases such as epithelial cancer, breast cancer, prostatic cancer,head and neck cancer and myeloid leukemias, for reversing and preventingatherosclerosis and restenosis resulting from neointimalhyperproliferation, for treating and preventing other non-malignanthyperproliferative diseases such as endometrial hyperplasia, benignprostatic hypertrophy, proliferative vitreal retinopathy and dysplasias,for treating autoimmune diseases and immunological disorders (e.g. lupuserythematosus) for treating chronic inflammatory diseases such aspulmonary fibrosis, for treating and preventing diseases associated withlipid metabolism and transport such as dyslipidemias, for promotingwound healing, for treating dry eye syndrome and for reversing andpreventing the effects of sun damage to skin.

The compounds developed in the prior art with retinoid like properties,are, however, not without disadvantages. Several such prior artcompounds cause serious irritation when applied to the skin (which is animportant mode of application for treatment of skin conditions) andcause skin toxicity when administered orally as well. Many of the priorart compounds having retinoid like activity are teratogenic.Teratogenecity or teratogenic activity can be defined as an undesirableeffect of a drug on a developing fetus. It is generally accepted in theart that pregnant females, and even females who are not pregnant but inthe child-bearing age should avoid teratogenic drugs.

In light of the foregoing, there is a significant need in the prior artfor pharmaceutical compositions, methods of treatment and new chemicalentitities which are effective as treatment of the diseases andconditions for which retinoid like compounds are usually applied, andwhich have reduced or no teratogenic activity and cause no significantirritation on the skin.

With respect to specific compounds or classes of compounds havingretinoid like or other biological activity, the following examples arenoted.

German Patent DE 3316-932 A describes 1-phenyl-2-chromanyl-propylenederivatives and sulphur and nitrogen analogs. Specific examples of thisdisclosure are ethyl p-[(E)-2-(4,4-dimethyl-6-chromanyl, thiochromanylor 1,2,3,4-tetrahydro-6-quinolinyl)propenyl]-1-benzoate.

U.S. Pat. No. 4,826,984 describes benzopyranyl (chromanyl) andbenzofuranyl-propenyl benzoic acids and esthers thereof, an examplebeing ethyl -p-(2-(4,4-dimethyl chroman-6-yl)-propenyl benzoate.

European EP 130 795 A discloses 4,4-dimethyl-6-chromanyl alkenyl benzoicacid derivatives, thiochromanyl and tetrahydroquinolinyl analogs. The 2and 7 positions of the chroman, thiochroman and tetrahydroquinoline ringmoieties in these compounds are not substituted.

The publication WO 8500-806 A discloses 4,4.-dimethyl-chroman-6-yl and4,4-dimethyl-thiochroman-6-yl -ethenyl and 4,4-dimethyl-chroman-6-yl and4,4-dimethyl-thiochroman-6-yl- propenyl benzoic acid, its esters and thecorresponding thiophencarboxylic acid and other heterocyclic acidanalogs. The 2 position of the chroman or thiochroman ring isunsubstituted.

The publication EP 350 846 A disclosesp-(2-(3,4-dihydro-4,4-dimethyl-dihydrochroman-7-yl)-propeneyl]benzoicacid ethyl ester and related compounds,

The publication WO 8504 652 A discloses certain diaryl substitutedpropenyl compounds, an example being ethyl(E)-4-[2-(4-isopropylphenyl)-propenylbenzoate.

European patent EP 206 751 A discloses 2-substitutedphenyl-alkenyl-quinoline derivatives as inhibitors of leukotrienesynthesis. An examples of a compound of this reference are(E)-4-(3-(2-(quinolin-2-yl)-1-methylethenylphenoxy)butyric acid.

Published European patent application 0 098 591 A1 describesrodenticidal disubstituted propenyl compounds, an example of which isethylp-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenylbenzoate, and another example is ethyl6-[(E)-2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]nicotinate.

Great Britain Patent GB 2190-378 describestetramethyl-tetrahydronaphthylpropenylphenol compounds, examples ofwhich are ortho, meta or para(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl)phenol.

German Patent DE 3602-473 A discloses aralkenylphenol derivatives,examples of which are(E)-I-(4-hydroxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propeneand(E)-I-(4-methoxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propene.

European Patent EP 176 033 A discloses isoxazolylvinyl indane andtetrahydronaphthalene derivatives, an example of which is(E)-5-[2-(3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-l-propenyl]-isoxazole-3-carboxylic acid.

The publication EP 303 915 discloses indanyl and tetrahydronaphthyl andsubstituted phenyl propenes as retinoids, where the phenyl substituentis sulfur substitited. An example of the disclosed compounds is methyl4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl(propenyl)phenylsulphone.

European patent EP 176 032 A discloses 6-styryltetrahydro-naphthalenederivatives, examples of which are(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-7-hydroxy-2-naphthalenyl)-l-propenyl]benzylalcohol, andE-4-[2-(5,8-dihydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoicacid.

European Patent EP 315 071 discloses1-benzocycloheptenyl-2-carboxy-phenyl ethylene derivatives, an exampleof which is ethylp-(E)-2-(6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocycloheptene-2-yl)propenylbenzoate.

German Patent DE 3524-199-A discloses stilbene-4-carboxylic acidderivatives, examples of which are [E-2-(3,4-diisopropylphenyl)propenyl]benzoic acid, [E-2-(3-tert-butylphenyl)propenyl] benzoic acid.

European Patent EP 245 825 describes heterocyclylalkenyl benzenederivatives, examples of which are 3- (β- ( 4'-hydroxy-3'-methoxyphenyl) ethenyl ) -5-methylpyrazole and 5- (β-(4'-hydroxy-3', 5'-his-(1,1-dimethylethyl)phenyl)-ethenyl)-5-methylpyrazole.

European Patent EP 210 929 A discloses certain 2-aryl-naphthalenederivatives useful in dermatological and ophthalmologycal medicaments.Intermediates leading to the synthesis of these compounds includecertain arylethenyl benzene derivatives.

German Patent DE 3531 722 A discloses certain benzonorbornenederivatives which have vitamin A like activity.

Great Britain patent GB 2164-938 A discloses certain2-styryl-naphthalene derivatives having retinoid like activity. Anexample of the compounds is 2-(4-methyl-β-methyl-styryl)naphthalene.

U.S. Pat. No. 4,326,055 discloses ethene derivatives which have asubstituted phenyl ring and a substituted indane or tetrahydronaphtalenegroup. The compounds are described as tumor inhibiting agents, anduseful for treating dermatological conditions and rheumatic illnesses.

U.S. Pat. No. 4,723,028 discloses 1,2-diphenylethene (stilbene)derivatives which have retinoid like activity.

U.S. Pat. No. 4,740,519 discloses certain aromatic heterocyclederivatives which have retinoid like activity.

Published European Patent Application 0130795 discloses ethenederivatives, where the ethene moiety is substituted by a substitutedphenyl group and by a substituted chroman, thiochroman or quinolinegroup. The compounds are useful for inhibiting the degradation ofcartilage in mammals.

Several co-pending applications and recently issued patents of thepresent inventor, which are assigned to the assignee of the presentapplication, are directed to further compounds having retinoid likeactivity.

SUMMARY OF THE INVENTION

It has been discovered in accordance with the present invention that thepartial structure or moiety shown in Formula 1 below, impartssignificantly reduced teratogenic activity, and reduces skin toxicity ina class of disubstituted ethene compounds which have retinoid like orrelated biological activity. ##STR2## In Formula 1 the partially drawnring signifies an aromatic ring which may be carbocyclic orheteroaromatic, 6-membered or 5-membered, and may be condensed withanother ring as particularly described below. R₁ is lower alkyl, Cl, Br,or I, R₂ is H, lower alkyl, Cl, Br, or I, and R₃ is lower alkyl, Cl, Br,I, or is an ether, thioether, ester, thioester, amine or substitutedamine group. It is an important feature of the present invention thatthe ethene moiety (double bond) is connected to an aromatic ring wherethe aromatic carbon adjacent to the carbon directly connected to thedouble bond (in other words the carbon in the ortho position) has asubstituent (R₃) with some steric bulk (other than hydrogen) and thatthe carbon of the olefinic double bond which is attached to the orthosubstituted aromatic ring is also substituted with a substituent (R₁)other than hydrogen.

In light of the foregoing, the present invention covers a method oftreating animals of the mammalian species, including humans, andparticularly females of child-bearing age and pregnant females, with anonteratogenic pharmaceutical composition comprising one or morecompounds of Formula 2 or of Formula 3 as the active ingredient, fortreatment of the diseases or conditions against which retinoid likecompounds are useful, namely as regulators of cell proliferation anddifferentiation, and particularly as agents for treating dermatoses,such as ache, Darier's disease, psoriasis, icthyosis, eczema and atopicdermatitis, and for treating and preventing malignant hyperproliferativediseases such as epithelial cancer, breast cancer, prostatic cancer,head and neck cancer and myelorid leukemias, for reversing andpreventing atherosclerosis and restenosis resulting from neointimalhyperproliferation, for treating and preventing other non-malignanthyperproliferative diseases such as endometrial hyperplasia, benignprostatic hypertrophy, proliferative vitreal retinopathy and dysplasias,for treating autoimmune diseases and immunological disorders (e.g. lupuserythematosus, for treating chronic inflammatory diseases such aspulmonary fibrosis, for treating and preventing diseases associated withlipid metabolism and transport such as dyslipidemias, for promotingwound healing, for treating dry eye syndrome and for reversing andpreventing the effects of sun damage to skin.

The present invention is also directed to the pharmaceuticalcompositions used in the above-noted methods of treatment. ##STR3##

The present invention particularly covers methods for treating diseasesand conditions where retinoid like compounds are effective fortreatment, but their use is limited because of their generally knownskin toxicity. ##STR4##

In Formula 2 the symbols are defined as follows:

R₁ is lower alkyl, Cl, Br, or I;

R₂ is H, lower alkyl, Cl, Br, or I;

R₃ is lower alkyl, Cl, Br, I, OR₁₁, SR₁₁, OCOR₁₁, SCOR₁₁, NH₂, NHR₁₁,N(R₁₁)₂, NHCOR₁₁, or NR₁₁ --COR₁₁ ;

R₅ and R6 independently are H, lower alkyl, Cl, Br, I, lower alkoxy orlower thioalkoxy of 1 to 6 carbons, or R₆ is absent;

A is (CH₂)_(n) where n is 0-5, lower branched chain alkyl having 3 to 6carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbonsand 1 or 2 double bonds, alkynyl having 2 to 6 carbons and i or 2 triplebonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, --COR₇, CR₇ (OR₁₂)₂, or CR₇ OR₁₃ O, where R₇ is an alkyl, cycloalkylor alkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl orlower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl groupof 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenylor lower alkylphenyl, R₁₁ is alkyl of 1 to 10 carbons, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons;

X₁ is CR₅ or N, and in case X₁ is N it can be located in anyunsubstituted position of the 6-membered aromatic ring;

Y is phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, thiazolyl, imidazolyl and oxazolyl, and

Z represents independently H, or one or two substituents being loweralkyl, lower alkoxy, lower thioalkoxy, lower alkenyl having one or moredouble bonds, lower alkenyloxy having one or more double bonds, or lowerthioalkenyloxy having one or more double bonds, or

Z represents --(CR₁₄)₄ --, or

Z represents --(CR₁₄)=(CR₁₄) --C(R₁₄)₂ --, or

Z represents --(CR₁₄)₃ --N--, or

Z represents --(CR₁₄)=(CR₁₄)--X₂ --, or

Z represents --C(R₁₄)₂ --C(R₁₄)₂ --X₂ --, or

Z represents --C(R₁₄)₂ -CR₁₄ =CR₁₄ --X₂ --, or

Z represents --C(R₁₄)₂ -C(R₁₄)₂ --C(R₁₄)₂ --C(R₁₄)₂ --, or

Z represents --C(R₁₄)₂ -C(R₁₄)₂ -C(R₁₄)₂ -X₂ --where

R₁₄ independently is H, lower alkyl, lower alkoxy, lower thioalkoxy, Cl,Br, or I, X₂ is O, S, or NR₁₅ and R₁₅ is H or lower alkyl.

In Formula 3 the symbols R₁, R₂, R₃, R₅, Y, A, B, and Z are defined asin connection with Formula 2, or R₅ may be absent; the dashed circle inthe 5 membered ring indicates the presence of two double bonds in the 5membered ring, and

X₃ is O, S, NH or N-lower alkyl, and the X₃ group can be located in anyunsubstituted position of the 5-membered aromatic ring.

New chemical compounds of the present invention are characterized byFormula 4, 5 and 6. ##STR5##

In Formula 4 R₁, R₂, R₃, R₅, R₆, A and B are defined as in connectionwith Formula 2.

R₂₀ is independently H or lower alkyl, and

Y₁ is thienyl, furyl or pyridyl. ##STR6##

In Formula 5 R₁, R₂, R₃, R₅, R₆, A and B are defined as in connectionwith Formula 2; R₂₀ is defined as in Formula 4;

Y₂ is phenyl, thienyl, furyl or pyridyl, and

X₄ is S, O, NH or N-lower alkyl. ##STR7##

In Formula 6 R₁, R₂, R₃, A and B are defined as in connection withFormula 2;

Y₂ is phenyl, thienyl, furyl or pyridyl, and

R₂₁ and R₂₂ are H or lower alkyl, with the proviso that both of thesesubstituents are not H.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1a is a graph showing the concentration of compound AGN 191701 FIG.16 in nanograms per ml, or nanograms per gram as indicated on the chart,in the plasma and embryo of mice at various times after oral intubationof a single dose of 10 mg/kg of the compound.

FIG. 2a is graph showing as percentage of control, the incorporation of³ H-thymidine (a measure of DNA synthesis) as a function ofconcentration of test compounds and a reference compound as shown inFIGS. 2b, 2c and 2d . The X-axis plots molar concentration of retinoidcompounds on a logarithmic scale.

FIG. 3a is a graph showing the results of the HL 60 Cell NBT Reduction(cell differentiation) assay with compound AGN 191440 FIG. 3b (Compound11).

FIG. 4a is a graph showing the results of the HL 60 Cell NBT Reduction(cell differentiation) assay with compound AGN 191701 FIG. 4b (Compound19).

FIG. 5a is a graph showing the results of the HL 60 Cell NBT Reduction(cell differentiation) assay with compound AGN 191768 FIG. 5b (Compound15).

FIG. 6a is a graph showing the results of the HL 60 Celltransglutaminase assay for prior art compound AGN 191183 and also forAGN 191440FIG. 6b (Compound 11).

FIG. 7a is a graph showing the results of the HL 60 Celltransglutaminase assay for AGN 191642FIG. 7b (Compound 13).

FIGS. 8a is a graph showing the results of the HL 60 Celltransglutaminase assay for AGN 191701FIG. 8b (Compound 19).

FIGS. 9a is a graph showing the results of the HL 60 Celltransglutaminase assay for AGN 191659 FIG. 4b (Compound 21).

GENERAL EMBODIMENTS Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branch-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Loweralkyl means the above-defined broad definition of alkyl groups having 1to 6 carbons, and as applicable, 3 to 6 carbons for branch chained andcyclo-alkyl groups. Lower alkenyl is defined similarly having 2 to 6carbons for normal alkenyl, and 3 to 6 carbons for branch chained andcycloalkenyl groups.

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where B (of Formula 2, 3, 4, 5 and 6) is --COOH, this termcovers the products derived from treatment of this function withalcohols, preferably with aliphatic alcohols having 1-6 carbons. Wherethe ester is derived from compounds where B is --CH₂ OH, this termcovers compounds of the formula --CH₂ OOCR₁₁ where R₁₁ is anysubstituted or unsubstituted aliphatic, aromatic or aliphatic-aromaticgroup, preferably with 1-6 carbons in the aliphatic portions.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids oralcohols. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance includes the unsubstituted amides and allaliphatic and aromatic mono-and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals include the radicals of the formula --CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound usedin the method of treatment of this invention, if the compound has afunctionality capable of forming such salt, for example an acid or anamine functionality. A pharmaceutically acceptable salt may be any saltwhich retains the activity of the parent compound and does not impartany deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The compounds utilized in accordance with the method of treatment of thepresent invention, as well as those compounds of the present inventionwhich comprise novel composition of matter, contain at least one doublebond and therefore may have trans and cis (E and Z) isomers. Inaddition, some of the compounds used in the method of treatment of thepresent invention may contain one or more chiral centers and thereforeexist in enantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all such isomers per se, as well asmixtures of cis and trans isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well.

METHODS OF ADMINISTRATION

The compounds used in the method of treatment of this invention may beadministered systemically or topically, depending on such considerationsas the condition to be treated, need for site-specific treatment,quantity of drug to be administered, and similar considerations.

In the treatment of dermatoses particularly, topical administration maybe used, though in certain cases such as treatment of severe cysticacne, oral administration may be preferred. Any common topicalformulation such as a solution, suspension, gel, ointment, or salve andthe like may be used. Preparation of such topical formulations are welldescribed in the art of pharmaceutical formulations as exemplified, forexample, by Remington's Pharmaceutical Science, Edition 17, MackPublishing Company, Easton, Pa. For topical application, these compoundscould also be administered as a powder or spray, particularly in aerosolform.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoid like compounds will be effectedby administration of the therapeutically effective dose of one or morecompounds in accordance with the instant invention. A therapeuticconcentration will be that concentration which effects reduction of theparticular condition, or retards its expansion. In certain instances,the drug potentially could be used in a prophylactic manner to preventonset of a particular condition. A given therapeutic concentration willvary from condition to condition and in certain instances may vary withthe severity of the condition being treated and the patient'ssusceptibility to treatment. Accordingly, a given therapeuticconcentration will be best determined at the time and place throughroutine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or other such dermatoses, that aformulation containing between 0.001 and 5 percent by weight, preferablyabout 0.01 to 1% will usually constitute a therapeutically effectiveconcentration. If administered systemically, an amount between 0.01 and100 mg per kg body weight per day, but preferably about 0.1 to 10 mg/kg,will effect a therapeutic result in most instances.

BIOLOGICAL ACTIVITY

The compounds used in the method of treatment of the present inventionhave no teratogenic activity, or are substantially less teratogenic thancomparable prior art compounds. The lack of teratogenecity of thesecompounds is demonstrated by an in vivo teratology study involvinggestating ICR mice. The methodology of the study is described asfollows:

ANIMALS

ICR mice (Ace Animals, Boyertown, Pa.) were used. Mature male and virginfemale ICR mice were housed in environmentally controlled rooms andacclimatized to a 12 hour light/dark cycle (light cycle 6 A.M. to 6P.M.) for 2 weeks prior to use. All animals were maintained on PurinaLab Chow and tap water ad libitum. A group of 3-4 females was caged witha single male of proven fertility for 4 hours. Presence of a vaginalplug immediately afterward was regarded as evidence of successfulmating, and this day was designated as day 0 of gestation.

TERATOLOGY

A single oral dose (0.1, 1.0, 10 or 100 mS/kS) of the test drug wasadministered on the morning (10 A.M.) of day 11 of gestation. Allanimals were killed by cervical dislocation under mild ether anesthesiaon day 17 of gestation. Upon laparotomy, the fetuses were examined forexternal malformations and weighed; one-half of each litter was thenfixed in 95% ethanol and processed for staining of the skeleton by therapid, alizarin red-S dye method. These preparations were examined undera dissection microscope to screen for abnormalities in the axial and theappendicular skeleton. The other half of each litter was fixed inBouin's solution and examined by freehand razor serial sectioning toscreen for anomalies of the brain, face, and palate.

Differences in dose-related incidence of malformations and resorptionswere assessed by computing percentages of affected conceptuses amongtotal implantation sites. The groups were compared statistically by amethod based on Student's t-tests of arcs in square root transformedpercentages. Values at 0.05 probability level were consideredsignificant. The median effective dose was calculated by logarithmiccurve fitting of the dose-response data.

                                      TABLE 1                                     __________________________________________________________________________                                  Teratogenic Effect                                            #    #          %    %                                                  Dose  Litters                                                                            Litters                                                                             %    Cleft                                                                              Limb                                       Compound                                                                              (mg/kg)                                                                             Treated                                                                            Normal                                                                              Resorbed                                                                           Palate                                                                             Defects                                    __________________________________________________________________________    AGN 191440                                                                            1     7    5     19   13   17                                         (Compound 11)                                                                         10    8    1      2   88   75                                                 100   3    0     100  --   --                                         AGN 191183                                                                            0.01  5    2      3   29   20                                         (prior art)                                                                           0.1   4    0     30   100  100                                                1     2    0     100  --   --                                                 10    2    0     100  --   --                                         AGN 191701                                                                            1     1    1     18    0    0                                         (Compound 19)                                                                         10    3    3     14    0    0                                                 100   3    2      2   19   22                                         __________________________________________________________________________

Results of the study are indicated in Table 1. As it can be seen fromTable 1. the compound designated AGN 191183 is a prior art compoundhaving the structure shown by Formula 7. The compound of Formula 7 doesnot have the moiety required for reduced teratogenecity (or lack ofteratogenecity) as required in accordance with the present invention andshown for example, in Formula 1. The data for this compound indicatesignificant teratogenecity; when the compound was given in a single doseof 0.1 mg/kg all the litters (100% exhibited teratogenic effects. Incontrast with the foregoing, two examplary compounds of the presentinvention (Compound AGN 191440 also designated in this application asCompound 11 and AGN 191701 also designated in this application asCompound 19) are significantly less teratogenic. Compound AGN 191440 wasapproximately 100 times less teratogenic than AGN 191183, (for exampleAGN 191440 at 1 mg/kg produced less teratogenic effects than AGN 191183at 0.01 mg/kg) and AGN 191701 was approximately 10⁴ times lessteratogenic than AGN 191183 (for example AGN 191701 at 100 mg/kgproduced less teratogenic effects than AGN 191183 at 0.01 mg/kg).##STR8##

In an in vitro bioassay which measures inhibition of chondrogenesis(bone formation) in chick embryo cells as a classic measure ofteratogenecity the results shown in Table 2 were obtained. The assay isdescribed as follows:

High-density "spot" cultures of limb bud mesenchymal cells were used tocompare the ability of various concentrations of test drugs to suppresschondrogenic differentiation as a bioassay. Forelimb buds of mouseembryos on day 12 of gestation (54±2 somites) were dissociated in atrypsin-EDTA solution, and the resultant single-cell suspension wasplated as 20-μl spots (200,000 cells/spot) on plastic culture dishes.Retinoid concentrations ranging from 0.3 ng/ml to 3 μg/ml (1 nM-10 μM)were added to the culture medium (Eagle's MEM+10% fetal bovine serum,GIBCO) 24 hours after initial plating. Control cultures received onlythe vehicle (ethanol, concentration ≦1% by vol); Retinoic acid was usedas a positive control in another set of cultures.

The cultures were terminated 96 hours after plating, at which time themedium was removed and the cells were fixed for 1 hour in 10% formalincontaining 0.5% cetylpyridinium chloride. The cultures were rinsed inacetic acid and stained for 1 hour in 0.5% Alcian blue solution at pH1.0, differentiated in 3% acetic acid, and then dehydrated in ethanoland scored for chondrogenesis under the microscope. An absence orreduction in the number of cartilage nodules in stained cultures ascompared with control cultures was taken as a measure of suppression ofchondrogenesis. The number of cartilage nodules stained in the wholespot, mean number of nodules, and standard deviations were calculatedfor four replicate cultures per treatment. The median concentrationcausing a 50% inhibition of chondrogenesis compared with controls (IC₅₀)was calculated by logarithmic curve fitting of the dose-response data.

As it can be seen in Table 2, the prior art compound AGN 191183 had anIC₅₀ concentration (concentration which inhibited chondrogenesis by 50%)which is approximately 1000 times less than the IC₅₀ of compound AGN191440 in accordance with the invention, and approximately 6,000 timesless than compound AGN 191701 in accordance with the invention. Thus,the prior art compound AGN 191183 was demonstrated to be significantlymore potent as a teratogen than the compounds in accordance with theinvention.

                  TABLE 2                                                         ______________________________________                                        Compound            IC.sub.50 (μg/ml)                                      ______________________________________                                        AGN 191183 (prior art)                                                                             0.003                                                    AGN 191440 (Compound 11)                                                                          2.5                                                       AGN 191701 (Compound 19)                                                                          19.0                                                      ______________________________________                                    

A pharmacokinetic study involving the oral intubation of mice with a10mg/kg dose of compound AGN 191701 in accordance with the presentinvention, and subsequent measurement of the concentration of the drugin the maternal plasma and in the embryo, as shown in FIG. 1, revealsthat compound AGN 191701 (Compound 19) is in fact present in substantialconcentration in the maternal plasma and in the embryo. Yet, as the dataof Table 1 show this compound has very little teratogeneic effect. Incontrast, the teratogenecity of prior art compound AGN 191183 is so highthat even an undetectably low concentration of the drug already causesdefective embryos.

The retinoid like activity of the compounds used in accordance with themethod of treatment of the present invention and of the novel compoundsof the invention can be confirmed by several assay procedures. An assayinvolving human sebocyte cultures measures the inhibition of ³H-thymidine into cells, and thus measures inhibition of DNA synthesisand thus an antiproliferative effect on sebocyte (i.e. a sebostaticeffect). This assay is also considered a specific assay foreffectiveness of a compound as a potential anti-acne drug. The test isconducted as follows.

SOURCE OF SKINS

Face-lift or forehead reduction skins from cosmetic surgeries were usedas sources of human sebaceous gland cells (sebocytes).

ISOLATION OF SEBOCYTES

Isolated sebocytes were plated in type 1 collagen coated-dishes inDMEM/F12 (1:1) medium supplemented with 8% fetal bovine serum, 2% humanserum, 10 ng/ml epidermal growth factor, 1 nM cholera toxin, 1 μMhydrocortisone, and penicillin/streptomycin/amphotericin B. Secondarycultures were prepared by plating Dispase dissociated cells in collagencoated 24-well plates.

PROLIFERATION STUDIES (³ H-THYMIDINE INCORPORATION)

Sub-confluent secondary cultures were treated with the test compounds orethanol vehicle every 2-3 days for 8 days in the above medium from whichthe total serum concentration was reduced to 2% and hydrocortisone wasnot included. During the last 6 hours of treatment, the cultures werelabeled with 2 μCi/ml ³ -thymidine. DNA from the cells were extracted bythichoroacetic acid and perchloric acid, and assayed for radioactivityby scintillation counting and for content of DNA by the diphenylaminecolorimetric method. The results were expressed as CPM/μg DNA, or as percent of vehicle control which incorporated about 1,000-1,500 cpm/μg DNA.

As the graph of FIG. 2 shows, depicting the results of this test forcompounds AGN 191701 (Compound 19), AGN 191659 (Compound 21) and forprior art compound AGN 191183, the prior art compound is not effectivein this assay, whereas the examplary compounds of the invention areeffective.

Other assays in which the retinoid like activity of the compounds usedin accordance with the invention are confirmed are the HL-60transglutaminase induction and HL-60 differentiation assay, theprocedures of which are described as follows.

DIFFERENTIATION: HL-60 CELLS NITROBLUE TETRAZOLIUM REDUCTION ASSAY (NBTREDUCTION ASSAY)

HL-60 cells were grown as a suspension culture in T-162 CM² flasks inserum-free RPMI 1640 medium supplemented with insulin (5 μg/ml),transferrin (5 μg/ml), and selenium (3 nM). The cells (1×10⁵ /well in24-well dishes) were treated with serial dilutions of test compounds inthe above RPMI 1640 medium which was additionally supplemented with 0.2mM dibutyryl cyclic adenosine monophosphate, a component found to benecessary for efficient differentiation of the cells. Ethanol was usedin the vehicle control cultures. After 3 days of incubation at 37° C. ina 5% CO₂ incubatot, nitroblue tetrazolium (NBT) and tetradecanoylphorbolacetate (TAP), at final concentrations of 0.1% and 100 ng/ml,respectively, were mixed with the cells and incubated at roomtemperature for 15 to 30 minutes. Differentiated HL-60 cells acquired apurple deposit of formazan (NBT positive cells) from the reduction ofNBT. The cells were then fixed in 10% paraformaldehyde and pelleted bycentrifugation. The cell pellets were resuspended in a small volume ofphosphate buffer saline. The number of NBT positive cells and the totalnumber of cells of each cell suspension was determined by counting in ahemacytometer. The mean of quadruplicate cultures was expressed as percent of NBT positive cells.

As it will be readily understood by those skilled in the art,differentiation of cells in this assay is a marker of useful retinoidlike activity. The results of this assay for compounds AGN 191440(Compound 11); AGN 191701 (Compound 19), and AGN 191768 (Compound 15)are shown in the graphs of FIGS. 3 through 5, respectively.

TISSUE TRANSLUTAMINASE ASSAY (tTGASE) IN HL-60 CELLS

HL-60 cells were grown as a suspension culture in T-162 cm² flasks inserum-free RPMI 1640 medium supplemented with insulin (5 μg/ml),transfertin (5 μg/ml), and selenium (3 nM). The cells (1×10⁶ cells/well,in 6-well dishes) were treated with serial dilutions of test compoundsin the above RPMI 1640 medium which was additionally supplemented with 1nM dibutyryl cyclic adenosine monophosphate, a component found to benecessary for efficient differentiation of the cells. Ethanol was usedin the vehicle control cultures. After 1 days of incubation at 37° C. ina 7.5% CO₂ incubator, the cells were collected in a set of tubes andpelleted by centrifugation. The cells were lyzed in a buffer containing20 mM Tris-HCl, pH 7.5, i mM EDTA, and 0.5% Triton X-100. An aliquot ofthe cell lysate was assayed for tTGASE activity in a reaction mixturecontaining 20 mM Tris-HCl, pH 7.5, 5 mM CaCl₂ , 2 mg/ml dimethylcasein,15 mM B-mercaptoethanol and 50 μCi/ml [2,3-³ H] putrescinedihydrochloride. The reaction was carried out for 60 minutes in a 37° C.shaking water bath. The reaction was stopped by an addition of 10%trichloroacetic acid containing 0.1% putrescein. An aliquot of thestopped reaction mixture was spotted on Whatman 3 MM filter discs. Thefilter discs, along with the control blank filter discs, were washedtwice with 5% trichloroacetic acid containing 0.1% putrescein and twicewith methanol. After drying under a heat lamp, the radioactivity in thefilter discs was determined by scintillation counting. An aliquot of thecell lysates was also assayed for protection concentration by theBradford method (Bio-Rad). After subtracting the radioactivity from thecontrol blank filter discs, the data were calculated and expressed aspmol/min/mg protein.

As is well understood in the art, induction of tranglutaminase activityin the just-described assay is an early marker of retinoid likeactivity. The graph of FIG. 6 shows the results of this test for priorart compound AGN 191183 (Formula 7), and also for AGN 191440(Compound.11). It can be seen in the graph that in this particular assaythe prior art compound is inactive, and AGN 191440 is active. The graphsof FIGS. 7 through 9 show that other exemplary compounds of thisinvention (AGN 191642 (Compound 13), AGN 191701 (Compound 19), and AGN191659 (Compound 21)) are also active in this assay.

Another advantageous property of the compounds used in accordance withthe methods of treatment of the present invention (and of the novelcompounds of the invention) is that the compounds show significantlyless toxicity and cause significantly less skin irritation thancomparable compounds lacking the structural features in accordance withthe present invention. The lessened toxicity of the compounds used inaccordance with the methods of treatment of the present invention (andof the novel compounds of the invention as well) is very significant,because toxicity, and specifically irritation of skin is considered ageneral disadvantage of retinoid like compounds. Therefore, the factthat the structure shown in Formula 1 imparts significantly lessenedtoxicity and skin irritating effect to the compounds in accordance withthe present invention, is surprising and remarkable.

Specifically, tests to determine skin toxicity were performed on certainexamplary compounds in accordance with the present invention, and oncertain analogous compounds which lack the R₃ substituent in accordancewith Formula 1, 2 or 3. A "Two Week Acute Skin Toxicity Study ofMultiple Topical Applications in Female Hairless Mice" is conducted asfollows: a daily dose (expressed in nanomoles) of the "test compound" isapplied to the skin on the back of hairless mice (usually a test groupof 5 mice for a given compound). The daily dose of the test compound isapplied for 5 consecutive days, followed by two days when the testcompound is not administered, and is thereafter administered again for 4more consecutive days. On the 14th day the test animals if still alive,are sacrificed to perform certain studies and tests. In the meanwhilecertain tests and observations are made on a daily basis with respect tobody weight and skin condition. Skin condition is graded as"flaking/scaling" and "abrasion" on a scale of 0 to + 5 where thevarious numbers correspond to the following observations.

    ______________________________________                                        Primary Skin Irritation Scoring Scale                                                                  Grade                                                ______________________________________                                        Flaking/scaling                                                               No flaking                  0                                                 Very slight (few flakes)   +1                                                 Slight (˜25% or less)                                                                              +2                                                 Mild (greater than ˜25%, less than ˜50%)                                                     +3                                                 Moderate (greater than ˜50%, less than ˜75%)                                                 +4                                                 Severe (˜75% or more)                                                                              +5                                                 Abrasion                                                                      No abrasion                 0                                                 Very slight (One to two abrasions with                                                                   +1                                                 a slight pink color)                                                          Slight (One or more abrasions, dark pink color)                                                          +2                                                 Mild (greater than ˜25%, light red color)                                                          +3                                                 Moderate greater than ˜50%, red color)                                                             +4                                                 Severe (greater than ˜75%, deep red color)                                                         +5                                                 ______________________________________                                    

Results of these tests are summarized in Table 3, where daily dose isexpressed in nanomoles, weight loss of the test animals is inpercentages at the end of the 14 day test period, or at the time thetest animal expired, and mortality is expressed with the number ofanimals which died from a group of 5.

                  TABLE 3                                                         ______________________________________                                                 Daily   % Weight  Death/                                                                              Flaking/                                     Compound Dose    Change    Total Scaling                                                                              Abrasion                              ______________________________________                                        AGN191183                                                                                7.5   -2.3      0/5   +2     +1                                    "        25      -13.4     0/5   +4     +1                                    "        75      -29.8     5/5   +1     +1                                    "        80      -2.3      5/5   +1     +2                                    AGN191440                                                                              75      3.1       0/5   +2     +1                                    "        124     -2.7      0/5   +2     +1                                    "        1240    -19.5     3/5   +4     +2                                    AGN191548                                                                              300     N/A       2/5   +5     +2                                    AGN191549                                                                              300     3.6       0/5   +1      0                                    AGN191543                                                                              800     N/A       2/5   +3     +1                                    AGN191544                                                                              800     3.6       0/5   +1      0                                    AGN190316                                                                              55      -2.0      0/5   +3     +2                                    "        60      -28.9     3/5   +2     +3                                    AGN191422                                                                              60      0.64      0/5   +1     +2                                    "        64      1.5       0/5   +1     +1                                    ______________________________________                                    

AGN 191183 is the prior art compound of Formula 7; AGN 191440 isCompound 11 which is structurally identical in every respect with AGN191183 except that it has the methyl group in the 3-position of thetetrahydronaphthalene nucleus, and is therefore within the scope of thepresent invention. AGN 191549 is Compound 24. AGN 191548 is a compoundwhich is structurally identical in every respect with AGN 191549 exceptthat it lacks the methyl group in the 7-position of the chroman nucleus,and is therefore not within the scope of the present invention. AGN191544 is Compound 26. AGN 191543 is structurally identical in everyrespect with AGN 191544 except that it lacks the methyl group in thebenzene ring ortho to the double bond, and is therefore not within thescope of the present invention. AGN 191422 is Compound 10. AGN 190316 isstructurally identical in every respect with AGN 191422 except that itlacks the methyl group in the 3-position of the tetrahydronaphthalenenucleus, and is therefore not within the scope of the present invention.The data of Table 3 demonstrate that the compounds in accordance withthe present invention cause significantly less death and less skinirritation than the compounds of analogous structures which neverthelesslack the features of the invention.

PREFERRED EMBODIMENTS

Referring now to the generalized structural Formulas 2-6 and withreference to the symbol A in these structures, depicting in effect aside chain on a phenyl group or heterocyclic group (representedrespectively by Y, Y₁ or Y₂), compounds are preferred in the method oftreatment of the invention, and also among the novel compounds of theinvention, where A is (CH₂)_(n). Still more preferred are compoundswhere n is zero.

With respect to the symbol B in Formulas 2-6, compounds are preferred inaccordance with the invention where B is --COOH, or an alkali metal saltor organic amine salt thereof. Alternatively, compounds are preferredwhere B is represented by COOR₈ (ester where R₈ is lower alkyl) , CONR₉R₁₀ (amide) --CH₂ OH (alcohol), CH₂ OCOR₁₁, CH₂ OR₁₁ (R₁₁ is loweralkyl; lower alkyl esters and ethers formed with a lower alkanol) or Bis --CHO or CH(OR₁₂)₂, CHOR₁₃ O (acetal derivatives), where R₁₂ and R₁₃are defined as in connection with Formula 2.

With respect to the symbol Y in Formulas 2 and 3, compounds arepreferred in accordance with the methods of treatment of the presentinvention where Y is phenyl, pyridyl, thienyl or furyl. With respect toFormula 4, depicting novel compounds in accordance with the invention,the preference is for Y₁ being thienyl. In Formula 5 and 6 which alsodepict novel compounds in accordance with the invention, the preferenceis for compounds where Y₂ is phenyl, thienyl or pyridyl.

With respect to the symbol R₂ in Formulas 2-6, R₂ is preferably hydrogenor lower alkyl, more preferably hydrogen.

As it was noted above, the substituent R₁ cannot be hydrogen inaccordance with the present invention. R₁ is preferably lower alkyl, andmost preferably methyl throughout the structures shown in Formulas 2-6.Similarly, R₃ cannot be hydrogen in accordance with the invention. Thissubstituent is preferably lower alkyl or halogen, and most preferablymethyl, chloro or bromo.

In Formulas 2-5 the R₅ and R₆ substituents (as applicable) arepreferably hydrogen or lower alkyl, more preferably hydrogen, or R₅ andR₆ are absent.

With respect to the symbol X₁ in Formula 2, compounds are preferred inthe method of treatment of the present invention where X₁ is CRS, andmost preferred where X₁ is CH. In Formula 3 X₃ is preferably sulfur.

With regard to the symbol Z in Formula 2 and 3, and more particularly inFormula 2, Z preferably represents a hydrogen and a lower alkyl group,or two lower alkyl groups, a hydrogen and a lower alkoxy group or twolower alkoxy groups, a hydrogen and a lower thialkoxy group or two lowerthioalkoxy groups, or a hydrogen and a lower thioalkeneoxy group havingone double bond. Alternatively, Z preferably represents --(CR₁₄)₄ --,--C(R₁₄)₂ --C(R₁₄)₂ --C(R₁₄)₂ --C(R₁₄)₂ --, or --C(R₁₄)₂ --C(R₁₄)₂--C(R₁₄)₂ --X₂ --. Among these compounds those are preferred where R₁₄is hydrogen or lower alkyl, most preferably methyl, and X₂ is preferablyO, or S. Still more preferred, in connection with the symbol Z inFormula 2 are the compounds where Z represents one of the following:C(CH₃)₂ --CH₂ --CH₂ --C(CH₃)₂-(3,5,5,8,8,-pentamethyl-tetrahydronaphthalene derivatives); C(CH₃)₂--CH₂ --CH₂ --O--(4,4,7-trimethyl-2,3-dihydrochroman derivatives);C(CH₃)₂ --CH₂ --CH₂ --S-- (4,4,7-trimethyl-2,3-dihydrothiochromanderivatives); C(CH₃)₂ -CH₂ --C(CH₃)₂ --O--(2,2,4,4,7-pentamethyl-2,3-dihydrochroman derivatives), and C(CH₃)₂--CH₂ --C(CH₃)₂ --S--(2,2,4,4,7-pentamethyl-2,3-dihydrothiochromanderivatives).

With regard to Formula 4 and 5, the symbols R₂₀ preferably representlower alkyl groups, and most preferably methyl groups. With respect toFormula 6 one of R₂₁ and R₂₂ is preferably branch chained lower alkylgroup, most preferably a t-butyl group.

The most preferred compounds used as substantially non-teratogenic andnon-irritating retinoid like therapeutic agents in the method oftreatment of the present invention are, with reference to Formula 8, 9,10, and 11,are as follows. ##STR9##

With reference to Formula 8:

    ______________________________________                                        Compound #      R.sub.3   X.sub.6  R.sub.8                                    ______________________________________                                        10              CH.sub.3  CH       Et                                         11              CH.sub.3  CH       H                                          12              Cl        CH       Et                                         13              Cl        CH       H                                          14              Br        CH       Et                                         15              Br        CH       H                                          16              CH.sub.3  N        Et                                         17              CH.sub.3  N        H                                          ______________________________________                                         ##STR10##

With reference to Formula 9:

    ______________________________________                                        Compound #  X.sub.7   R.sub.8                                                 ______________________________________                                        18          S         Et (COOR.sub.8 in position 4)                           19          S         H (COOR.sub.8 in position 4)                            20          S         Et (COOR.sub.8 in position 5)                           21          S         H (COOR.sub.8 in position 5)                            22          O         Et (COOR.sub.8 in position 5)                           23          O         H (COOR.sub.8 in position 5)                            ______________________________________                                         ##STR11##

With reference to Formula 10:

    ______________________________________                                        Compound #              R.sub.8                                               ______________________________________                                        24                      Et                                                    25                      H                                                     ______________________________________                                         ##STR12##

With reference to Formula 11:

    ______________________________________                                        Compound #    R.sub.8 t-butyl group in position                               ______________________________________                                        26            Et      3 to vinyl group                                        27            H       3 to vinyl group                                        28            Et      4 to vinyl group                                        29            H       4 to vinyl group                                        ______________________________________                                    

Synthetic Procedures for Obtaining the Compounds in Accordance with theInvention

The novel compounds of the invention as well as the compounds which areused in accordance with the novel method of treatment of the presentinvention can be made by a number of different synthetic chemicalpathways. To illustrate the invention the following synthetic schemesare provided. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments for making novelcompounds of the invention which can be generalized to any and all novelcompounds described in the present specification, and further that theconditions can be generalized to obtain any and all compounds which areto be used as non-teratogenic pharmaceutically active agents in themethods of treatment of the present invention. ##STR13##

Referring to Reaction Scheme 1, the synthesis of the phenyl-propenyl5,6,7,8-tetrahydronaphthalene compounds utilized in the method of thepresent invention is illustrated. In accordance with Reaction Scheme 1,a 5,5,7,8-tetrahydronaphthyl compound which has the desired R₃, R₅, R₆and R₂₀ substituents (as these are defined in connection with Formula 4)is reacted under Friedel Crafts-like conditions with a reagent such asR₁ COCl (R₁ is defined as in connection with Formula 4) to introduce theR₁ --CO-- ketone function into the 2-position of the naphthalenenucleus. When R₁ is methyl, then the reagent in the Friedel Crafts typereaction is typically acetyl chloride. The resulting ketone of Formula16 is then subjected to a Wittig Horner type reaction with a phosphonatereagent of Formula 17. The phosphonate reagent of Formula 17 carries anester (COOR₈) substituent, but it should be understood that an analogousphosphonate reagent can, generally speaking, carry the A-Bfunctionality, as such functionality is defined in connection withFormula 2. The Wittig Horner type reaction is conducted in the presenceof strong base, such as NaCH₂ SOCH₃ (dimsyl sodium) in a solvent liketetrahydrofuran (THF), as is indicated in the reaction scheme. Theethylenic bond (double bond) of the compounds of Formula 18 is formed inthis reaction. As is stated above, this double bond is a requiredfeature of the compounds used in accordance with the present invention.

The compounds of Formula 18 may be subjected to further transformations,particularly as far as synthetic transformation of the COOR₈ group isconcerned. As far as the synthesis of compounds analogous to thecompounds of Formula 18, but differring therefrom in the functionalityof the A-B group (see for example Formula 2) is concerned, (and byextension of the principles to any and all compounds used in accordancewith the invention) the following further well known and publishedgeneral principles and synthetic methodology are noted.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry, " 2nd Edition McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of n before affecting the Wittig Horner (oranalogous) coupling reaction of Reaction Scheme 1 (where such compoundscorresponding to Formula 17 are not available from a commercial source)aromatic or heteroaromatic carboxylic acids are subjected tohomologation by successive treatment under Arndt-Eistert conditions orother homologation procedures. Alternatively, derivatives which are notcarboxylic acids may also be homologated by appropriate procedures. Thehomologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

An alternative means for making compounds where A is (CH₂)_(n) (n is1-5) is to subject the compounds of Formula 2, (or of Formula 18) whereB is an acid or other function, to homologation, using the Arndt-Eistertmethod referred to above, or other homologation procedures.

Compounds of Formula 2, where A is an alkenyl group having one or moredouble bonds can be made for example, by having the requisite number ofdouble bonds incorporated into the intermediate which is coupled as aphosphonate with the ketone of Formula 16. Generally speaking, suchcompounds where A is an unsaturated carbon chain can be obtained bysynthetic schemes well known to the practicing organic chemist; forexample by Witrig and like reactions, or by introduction of a doublebond by elimination of halogen from an alpha-halo-arylalkyl-carboxylicacid, ester or like carboxaldehyde. Compounds of Formula 2 where the Agroup a triple (acetylenic) bond can be made by using the correspondingphosphonate intermediate. Such intermediate can be obtained by reactionswell known in the art, for example, by reaction of a correspondingaromatic-methyl ketone with strong base, such as lithium diisopropylamide.

The acids and salts derived from compounds of Formula 2 and of Formula18 are readily obtainable from the corresponding esters. Basicsaponification with an alkali metal base will provide the acid. Forexample, an ester of Formula 2 or of Formula 18 may be dissolved in apolar solvent such as an alkanol, preferably under an inert atmosphereat room temperature, with about a three molar excess of base, forexample, potassium hydroxide. The solution is stirred for an extendedperiod of time, between 15 and 20 hours, cooled, acidified and thehydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethlaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds of Formula 2 where B is H can be prepared from thecorresponding halogenated aromatic compounds, preferably where thehalogen is I. ##STR14##

Reaction Scheme 2 illustrates another example of a synthetic procedurefor preparing the compounds used in accordance with the invention,specifically as applied for the synthesis of compounds where the Y groupin Formula 2 is heteroaryl, such as thienyl. Thus, in accordance withthis examplary reaction scheme, the ketone of Formula 16 is reduced (forexample with sodium borohydride) to the corresponding alcohol of Formula19. The alcohol of Formula 19 is converted to the correspondingphosphonium salt (for example triphenyl phosphonium bromide) bytreatment with the appropriate reagents, such as phosphorous tribromideand triphenylphosphine. The phosphonium salt of Formula 20 is a Wittigreagent, which is reacted with a bromo thiophene aldehyde of Formula 21,under Wittig conditions (base such as n-butyl lithium). The compound ofFormula 22 which is formed as a result of the latter reaction has theessential structural features of the compounds used in accordance withthe present invention, namely the R₁ substituent on the double bond, andthe R₃ substituent on the adjacent aromatic ring carbon, as well thearomatic or heteroaromatic group as yet another substituent on thedouble bond. The bromo group of the thiophene moiety of the compound ofFormula 22 is converted into a carboxyl group by reaction with t-butyllithium and capture of carbon dioxide. The compounds of Formula 23 areactive agents in accordance with the present invention, and can also beconverted into further homologs and derivatives, as described above.

An example of a variation of the procedure outlined in Reaction Scheme 2is a reaction between the triphenylphosphonium salt of Formula 20 and4-carbethoxybenzaldehyde by heating in 1,2-epoxybutane. This reaction isparticularly advantageously conducted when R₃ of Formula 16 is chloro.The products of these Wittig-type reactions are compounds which are usedin accordance with the methods of treatment of the invention; when R₂₀is methyl and R₃ is Cl, then the product is Compound 12. ##STR15##

Reaction Scheme 3 provides another example of preparing compounds inaccordance with the present invention by utilizing a Wittig Horner typereaction between a chroman derivative ketone of the Formula 24 and aphosphonate of the Formula 17. (R₁, R₃, and R₂₀ in Formula 24 aredefined the same as in connection with Formula 4.) The chromanderivative of Formula 24 can be obtained in accordance with theteachings of U.S. Pat. No. 4,980,369, and specifically as is describedwith reference to Reaction Scheme 2 in that patent, and in analogy tothe actual example provided in that reference patent for preparing2,2,4,4,7-pentamethyl-6-acetylchroman (Column 20 line 58). Thespecification of U.S. Pat. No. 4,980,369 is expressly incorporatedherein by reference. Thus, the chroman derivative of Formula 24 iscoupled in the presence of potassium bis(trimethylsilyl)amide intetrahydrofuran with the phosphonate of Formula 17 to yield thecompounds of Formula 25 which are active agents in accordance with thepresent invention. An example of a preferred compound in accordance withFormula 25 is Compound 24. The compounds of Formula 25 can also bederivatized or converted into homologs, as described above. For example,Compound 25 is obtained by saponification of Compound 24. ##STR16##

Reaction Scheme 4 illustrates another example of a synthetic route forobtaining the compounds of the present invention, particularly wherewith reference to Formula 2 the symbol Z represents one or two loweralkyl groups and X₁ represents CH, and specifically when Z represents at-butyl group.

In accordance with Reaction Scheme 4, the substituted acetophenone (R₁=CH₃), or acetophenone homolog of Formula 26 is reacted in a WittigHorner type reaction (such as in the presence of dimsyl sodium intetrahydrofuran) with the phosphonate of Formula 17. The compounds ofFormula a? obtained in this manner are active agents in accordance withthe invention. The compounds of Formula 27 can also be derivatized andconverted into homologs, as described above. Examples of preferredcompounds which are obtained in accordance with this reaction scheme areCompounds 26-29.

The foregoing synthetic routes together with the specific examples whichare provided below are believed to enable the practicing organic chemistto obtain any and all compounds which are active agents in accordancewith the methods of treatment of the present invention. Nevertheless, byway of further illustration and examples, the following is noted.Generally speaking, the compounds of the invention can be obtained inaccordance with the reactions set forth in Reaction Schemes 5-8.##STR17##

The reaction shown in Reaction Scheme 5 is generally known in the art asa Wittig Horner reaction, sometimes this reaction is also referred to asthe Horner Emmons reaction. It involves the reaction of a ketone with aphosphonate under basic conditions to form an olefinic bond, inaccordance with the scheme, to provide the compounds of Formula 2. Thereactants in this reaction scheme are the aromatic or heteroaromaticketone of Formula 28 and the aromatic or heteroaromatic phosphonate ofFormula 29. The symbols in these formulas are defined as in connectionwith Formula 2. The heteroaromatic ketones of Formula 28 can, generallyspeaking, be obtained by procedures well known and published in thechemical literature; frequently such procedures involve the introductionof the R₁ CO group, (the CH₃ CO group when R₁ =CH₃) by a Friedel-Craftsor like reaction to the otherwise appropriately substituted aromatic orheteroaromatic compound. Actual examples for preparing phosphonatescorresponding to Formula 29 are provided below. Generally speaking, suchphosphonates can be obtained by reacting the alkylated aromatic orheteroaromatic compound having the structure R₂ -CH₂ Y-A-B withN-bromosuccinimide, and thereafter reacting the resulting bromo compoundR₂ -CHBrY-A-B with triethylphosphite. Generally speaking, the WittigHorner reaction illustrated in Reaction Scheme 5 is the preferredprocedure for preparing the compounds of Formula 2 and of Formula 3 aswell when the A-B functionality represents a reasonably strong electronwithdrawing group (such as an ester).

Reaction Scheme 6 illustrates an alternative route for utilizing theWittig Horner reaction for preparing the compounds of Formula 2 and byanalogy of Formula 3 as well. The symbols have the same definitions asin connection with Formula 2. In this reaction scheme, the phosphonateof Formula 30 is formed from the aromatic or heteroaromatic moiety whichis analogous to the compounds of Formula 28. The phosphonates of Formula30 can be derived, generally speaking, from the ketones of Formula 28through reduction, and conversion of the resulting alcohol into a halide(preferably bromide) and thereafter into the phosphonate. The aromaticor heteroaromatic aldehydes or ketones of Formula 31 can be obtained byprocedures readily available to the practicing organic chemist.

Reaction Scheme 7 illustrates another preferred general procedure forobtaining the compounds of Formula 2, and by analogy of Formula 3 aswell. The symbols in this reaction scheme are defined as in connectionwith Formula 2. In accordance with this procedure, a phosphonium salt,preferably a triphenylphosphonium salt of Formula 32, is obtained forexample from the ketone of Formula 28. The phosphonium salt of Formula32 can be obtained from the ketone compounds of Formula 28 by reductionto an alcohol, and subsequent reaction with phosphorous tribromide andtriphenylphosphine, in analogy to the reaction described in connectionwith Reaction Scheme 2. The phosphonium salt of Formula 32 is thereafterreacted with the aromatic or heteroaromatic aldehyde or ketone ofFormula 31 in a Wittig reaction, involving the action of strong base,such as n-butyl lithium.

Reaction Scheme 8 illustrates an alternative Wittig reaction as ageneral procedure for obtaining the compounds of Formula 2, and byanalogy of Formula 3 as well. The symbols in this reaction scheme aredefined as in connection with Formula 2. In accordance with thisprocedure the aromatic or heteroaromatic ketone of Formula 28 isreacted, in the presence of strong base with a phosphonium salt,preferably with a triphenylphosphonium bromide of Formula 33. Thetriphenylphosphonium bromide of Formula S3 can be obtained, for example,by reaction of the bromo compound R₂ -CHBrY-A-B with triphenylphosphine.

Examples of reagents in accordance with Formulas 29, 31 and 33 to beused in the Wittig Horner or Wittig and analogous coupling reactions toprovide the compounds used in the methods of treatment of the presentinvention, are as follows:

ethyl [4-(diethoxyphosphinyl)methyl]benzoate (Compound 40);

Diethyl (3-carboethoxybenzyl)phosphonate;

Diethyl (2-carboethoxybenzyl)phosphonate;

Diethyl (2-carboethoxy-5-thiophenyl)methylphosphohate (Compound 41)

Ethyl 2-[5-(diethoxyphosphinyl)methyl]furancarboxylate (Compound 42);

Ethyl-3-[5-[(diethoxyphosphinyl)methyl]]nicotinoate (Compound 43)

Examples of reagents in accordance with Formula 28, 30 and 32 to be usedin the Wittig Horner or Wittig and analogous coupling reactions toprovide the compounds used in the methods of treatment of the presentinvention, are as follows:

Methyl [3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone(Compound 50)

1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethan-1-yl-triphenylphosphonium bromide (Compound 51);

2,2,4,4,7-pentamethyl-6-acetylchroman (Compound 52) see U.S. Pat. No.4.980,369;

2-methyl-5-t-butylacetophenone (Compound 53); obtainable in accordancewith the chemical literature, J. Amer. Chem, Soc., 77, p 1696 (1955);Chem. Ber., 32, p 2422 (1899); J. Org. Chem., 22, pp 25-29 (1957);

Methyl [3-chloro-5,5,8,8-tetramethyl (5,6,7,8-tetrahydronaphthalen)-2-yl]ketone (Compound 54 );

[(5,6,7,8-tetrahydro-3-chloro-5,5,8,8-tetramethylnaphthalen-2-yl)ethan-l-yl]triphenylphosphoniumbromide (Compound 55);

2-methyl-4-t-butylacetophenone (Compound 56); obtainable in accordancewith the chemical literature, Chem. Ber., 31, p. 1345 (1898); J. Org.Chem., 22, pp 25,26 (1957); J. Chem. Soc., 1952, p. 1123;

Methyl[3-bromo-5,5,8,8-tetramethyl(5,6,7,8tetrahydronaphthalen)-2-yl]ketone(Compound 57);

Methyl[3-ethyl-5,5,8,8-tetramethyl-(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone(Compound 58);

Methyl 3-isopropyl[5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone (Compound59);

Ethanone, 1-(5,6,7,8-tetrahydro-2-methyl-3-quinolinyl), obtainable inaccordance with the chemical literature, CA79(13):78555k; Chem. Ber.106(6), 1736-42 (1973);

Ethanone, 1- (2-methyl-3-quinolinyl ), obtainable in accordance with thechemical literature, CA90(19) :152027k German Offenlegungsschrift DE2730061 Jan. 18, 1979;

Ethanone, 1- (3-methyl-2-naphthalenyl ), obtainable in accordance withthe chemical literature, CA111(19):173803c, Japanese Patent JP 01047734A2, Feb. 22, 1989;

Ethanone, 1-(2-methyl-1H-inden-3-yl), obtainable in accordance with thechemical literature, CA95(23):202928f, J. Org. Chew. 46(24), 5022-5(1981);

Ethanone, 1-(2-methyl-1H-indol-3-yl), obtainable in accordance with thechemical literature, CA115(15) :159291k, Tetrahedron 47(28) 5111-18(1991);

Ethanone, 1-(2-methylbenzo[b]thien-3-yl), obtainable in accordance withthe chemical literature, CA85(25):192542c, French Patent Application FR2279395 Feb. 20, 1976;

Ketone, methyl 4,5,6,7-tetrahydro-2-methylbenzo[b]thien-3-yl, obtainablein accordance with the chemical literature, Bull. Soc. Chim. France 3,359-361 (1958);

Ethanone, 1- (4,5,6,7-tetrahydro-2-methyl-3-benzofuranyl), obtainable inaccordance with the chemical literature, CA91(18):148446z, J. Org. Chem.44(20) 3519-23 (1979);

Ethanone, 1-(4,5,6,7-tetrahydro-2-methyl-1H-indol3-yl, obtainable inaccordance with the chemical literature, CA82(17):111890c, Ann. Chim.(Rome) 63(9-10) 601-6 (1973);

Thieno[2,3-b]pyridine, 7-acetyl-4,5,6,7-tetrahydro-2-methyl, obtainablein accordance with the chemical literature, CA110(15):135007t,Tetrahedron 44(15) 4777-86 (1988);

Ethanone, 1-[6-(methoxymethyl)-5-benzofuranyl ], obtainable inaccordance with the chemical literature, CA87(1):5839w, J. Chew. Soc.,Perkin Trans. 1(4), 423 (1977);

Ethanone, 1-(6-chloro-3-methyl-5-benzofuranyl), obtainable in accordancewith the chemical literature, CA78(17):110781y, Indian J. Chem. 10(11)1065-7 (1972).

Further examples of reagents in accordance with Formula 26 to be used inthe Wittig Horner or Wittig and analogous coupling reactions to providethe compounds used in the methods of treatment of the present invention,can be obtained in accordance with well known and establishedprocedures, for example by acylation (acetylation) under Fridel-Craftslike conditions of further known aromatic and heteroaromatic compounds,such as 6-methyl-benzofuran (CA103(9):71182s); 6-methyl-1H-indole(CA114(23):228730w) and 6-methylbenzo[b]thiophene (CA114(15):143128f).

SPECIFIC EXAMPLES 4-Carboethoxy-benzylbromide

To a stirred solution of 16.09 g (78 mmol) of1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride wasadded a suspension of 15.4 g (71 mmol) of 4-carboxybenzylbromide in 100ml methylene chloride and then 4.9 g (106.5 mmol) of absolute ethanoland 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml ofmethylene chloride was added to the reaction mixture and mixture heatedat reflux for 2 hours. The mixture was allowed to cool to roomtemperature and the resultant white precipitate removed by filtration.The filtrate was washed with water, dried (MgSO₄) and then concentratedin-vacuo to give the title compound as a colorless oil whichcrystallized on standing. PMR (CDCl₃); δ1.39 (3H, t, J˜7.2 Hz), 4.38(2H, q, J-7.2 Hz), 4.50 (2H, s), 7.45 (2H, d, J ˜7.7 Hz), 8.03 (2H, d,J˜7.7 Hz).

Ethyl [4- (diethoxyphosphinyl) methyl]benzoate (Compound 40)

A mixture of 11.8 g (48 mmol) of 4-carboethoxybenzylbromide and 12.0 g(72 mmol) of freshly distilled triethylphosphite was placed in a flaskfitted with an argon inlet and a dry-ice cooled trap. A continuousstream of argon was passed over the stirred reaction mixture and mixtureheated at 120˜° C. for 3 hours at which time no further ethyl bromidewas being formed. The residue was purified by vacuum distillation togive the title compound as a colorless oil, BP=170°/0.35 ram). PMR(CDCl₃): δ1.23 (6H, t, J ˜7.1 Hz), 1.39 (3H, t, J ˜6.9 Hz), 3.21 (2H, d,J ˜22.1 Hz), 4.02 (4H, m), 4.37 (2H, q, J ˜7.5 Hz), 7.38 (2H, d, J 187.9 Hz), 8.00 (2H, d, J ˜7.9 Hz).

Ethyl 5-methyl-2-thiophenecarboxylate

To a stirred solution of 15.9 g (77.4 mmol) of1,3-dicyclohexylcarbodiimide in 40 mL dichloromethane was added 10 g(70.3 mmol) of 5-methyl-2-thiophenecaboxylic acid and 4.85 g (105.5mmol) of anhydrous ethanol. 0.86 g of dimethylaminopyridine was thenadded and the suspension stirred at room temperature for 20 hours. Theresulting white precipitate was removed by filtration. The filtrate waswashed with water, dried (MgSO₄), filtered and concentrated underreduced pressure. The residue was purified by bulb-to-bulb distillation(bp=95° C. 3 mm Hg) to give the title compound as a clear, pale yellowoil.

PMR (CDCl₃): δ1.36 (3H, t, J=7.1 Hz), 2.52 (3H, s), 4.32 (2H, q, J =7.1Hz), 6.76 (1H, d, J =3.8 Hz), 7.61 (1H, d, J =3.8 Hz).

Ethyl 5-bromomethyl-2-thiophenecarboxylate

N-Bromosuccinimide (23.5 g, 132 mmol), benzoyl peroxide (0.26 g) and 90mL of benzene were brought to reflux under argon. Ethyl5-methyl-2-thiophenecarboxylate (22.5 g, 132 mmol) was added dropwisethrough an addition funnel and the resulting mixture was refluxed for 6hours and then cooled to room temperature and stirred for 16 hours. Themixture was treated with 50 mL of water and extracted with 3×75 mLether.

The ether extracts were combined and washed with 75 mL saturated aqueousNaCl and then dried (MgSO₄). The solvent was removed in-vacuo and theresidual oil purified by flash chromatography (SiO₂, 99:1, ethyl acetatein hexanes) to give the title compound as a clear, yellow oil.

PMR (CDCl₃): δ1.37 (3H, t, J=7.3 Hz), 4.35 (2H, q, J=7.3 Hz), 4.68 (3H,s), 7.09 (1H, d, J =4.0 Hz), 7.64 (1H, d, J =4.0 Hz).

Ethyl 5-[(diethoxyphosphinyl)methyl]-2-tiophenecarboxylate (Compound 41)

A mixture of 4.99 g (20.0 retool) of ethyl5-bromomethyl-2-thiophenecarboxylate and 5.17 mL (30.0 mmol) oftriethylphophite was heated to 120° C. under argon for 6 hours and theexcess triethylphosphite removed by distillation.

The product was purified by vacuum distillation (bp=175°, 3 mm Hg) togive the title compound as a clear, pale yellow oil.

PMR (CDCl₃): δ1.30 (6H, t, J=7.1 Hz), 1.37 (3H, t, J=7.2 Hz), 3.38 (2H,d, J =20.9 Hz), 4.05-4.15 (4H,m), 4.33 (2H, q, J =7.1 Hz), 6.99 (1H, dd,J =3.6, 3.6 Hz), 7.66 (1H, d, J=1.1, 3.6 Hz).

Ethyl 2-(5-bromomethyl)furancarboxylate

To a suspension of 1.32 g (7.4 retool) of N-bromosuccinimide and 10.9 mgof benzoyl peroxide in 8 mL of carbontetrachloride was added a solutionof ethyl-2-(5-methyl) furancarboxylate in 8 mL of carbon-tetrachlorideand the resulting mixture stirred at 55° C. for 8 hours. The mixture wasthen filtered, concentrated and residual oil purified using flashchromatography (SiO₂, 5% ethyl acetate in hexanes) to give the titlecompound as a clear oil.

Ethyl 2-[5-(diethoxyphosphinyl)methyl]furancarboxylate (Compound 42)

A solution of 1.84 g (1.30 ml, 14.8 mmol) of triethylphosphite and 0.84g (3.6 mmol) of ethyl2-(5-bromomethyl)furancarboxylate was heated at125° C. under argon for 30 hours. The solution was then cooled andpurified using kuegelrohr distillation (165°-180° C., 1 mm Hg) to givethe title compound as a clear oil.

Ethyl [5-bromomethyl]nicotinoate

To a solution of ethyl-3-[5-methyl]nicotinoate in 10 mL ofcarbontetrachloride was added 10.9 mg of benzoyl peroxide and a tipfullof N-bromosuccinimide. The mixture was heated to 60° C. and theremaining 1.19 g (6.7 mmol, total) of N-bromosuccinimide was taken-up in20 mL of carbontetrachloride and added to the heating mixture. Theresulting mixture was stirred ato 60° C. for 3 hours and at roomtemperature for 12 hours. Additional benzoyl peroxide was then added (9mg) followed by 4 hours of additional heating. The mixture was thencooled, filtered, concentrated and the residual oil purified using flashchromatography (SiO₂, 10% ethyl acetate in hexanes) to give the titlecompound as a pinkish solid.

Ethyl-3-[5-(diethoxyphosphinyl)methyl]nicotinoate (Compound 43)

A solution of 0.99 g (0.70 ml, 7.98 mmol) of triethylphosphite and 0.21g (8.6 retool) of ethyl-3-[5-bromomethyl]nicotinoate were heated at 130°C. under argon for 24 hours and at room temperature for 48 hours. Thesolution was then cooled and purified using kuegelrohr distillation(155°-165° C., 1 nun Hg) to give the title compound as a yellow oil.

Methyl [3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen)-2-yl] ketone(Compound 50)

To a suspension of 6.71 g (50.3 mmol) of aluminum chloride in methylenechloride at 0 ° C. under argon was added a solution of 3.95 g (3.58 mL,50.3 mmol) of acetyl chloride and 10.21 g (41.9 mmol) of3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene in methylenechloride. The resulting mixture was allowed to warm to room temperatureover a period of 3 hours with stirring. The mixture was recooled to 0°C. and 1N HCl was dropwise added. The mixture was then taken-up in waterand extracted three times with methylene chloride. The organic layerswere washed with 1N HCl, water, brine, and dried (MgSO₄). Solvent wasremoved in-vacuo and the resulting residue purified using flashchromatography to give the title compound as an ivory solid.

PMR (CDCl₃): δ1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 2.49 (3H, s),2.57 (3H, s), 7.15 (1H, s), 7.67 (1H, S).

Ethyl4-[(E)-2,(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]benzoate(Compound 10)

A solution of 5.0 q (21.5 mmol) of methyl[3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydro-naphthalen)-2-yl] ketone(Compound 50) and 3.39 g (11.3 mmol) of ethyl[4-(diethoxyphosphinyl)methyl]benzoate, (Compound 40) in 25 mL oftetrahydrofuran was added via cannula into a suspension of 0.52 g (21.5mmol) of sodium hydride in 25 mL of tetrahydrofuran at 0° C. underargon. The resulting suspension was allowed to warm to room temperatureand stirred for 16 hours. The resulting sludge was taken-up in water and1N HCl and extracted with ether. The ether layers were washed withwater, brine, and dried (MgSO₄). The solvent was removed in-vacuo andthe residue purified using flash chromatography (SiO₂, 1% ethyl acetatein hexanes) to give a mixture of isomers which were separated usingHPLC. (0.5% ethyl acetate in hexanes) to give the title compound as awhite solid.

PMR (CDCl₃): δ1.30 (12H, s), 1.38 (3H, t, J=7.0 Hz), 1.69 (4H, s), 2.21(3H, s), 2.30 (3H, s), 4.39 (2H, q, J=7.1 Hz), 6.42 (1H, s), 7.12 (2H,overl. s), 7.43 (2H, d, J=8.3 Hz), 8.05 (2H, d, J =8.3 Hz).

4-(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]benzoicacid (Compound 11)

A solution of potassium hydroxide in ethanol was added to 95 mg (0.25mmol) of ethyl4-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnapth)-2-yl)propen-1-yl]benzoate(Compound 10) and the resulting mixture stirred at room temperature.Solvent was removed in-vacuo and the resulting solid taken-up in water,acidified using 1N HCl, and extracted three times with ether. The etherextracts were washed with water, brine and dried (MgSO₄). The solventwas removed in-vacuo to give the title compound as an orange solid.

PMR (d⁶ -DMSO): δ1.23 (12H, s), 1.62 (4H, s), 2.15 (3H, s), 2.23 (3H,s), 6.37 (1H, s), 7.08 (1H, S), 7.13 (1H, s), 7.51 (2H, d, J=8.3 Hz),7.94 (2H, d, Hz).

2-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalen-2-yl)propen-1-yl]-4-bromothiopbene

To a solution of 0.56 g (0.98 mmol) of1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethan-1-yltriphenylphosphoniumbromide (Compound 51) in 11 mL of tetrahydrofuran at -78 ° C. underargon was added dropwise 0.41 g (0.61 mL, 0.98 mmol, 1.6 M in hexanes)of n-BuLi. The resulting suspension was allowed to warm to roomtemperature and then a solution of 0.28 g (1.47 mmol) of4-bromo-2-thiophenecarboxaldehyde in 2 mL of tetrahydrofuran wasdropwise added and the resulting mixture stirred for 20 hours at roomtemperature. The solvent was removed in-vacuo and the resulting solidtaken-up in water, acidified using 1N HCl, and extracted three timeswith ether. The ether extracts were washed with water, brine and dried(MgSO₄). The solvent was removed in-vacuo and resulting residue purifiedusing flash chromatography (SiO₂, 0.5 % ethyl acetate in hexanes) togive the title compound as a white solid.

PMR (CDCl₃): δ1.27 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 2.26 (6H, m),6.45 (1H, s), 6.75 (1H, s), 6.95 (1H, s), 7.07 (1H, s),. 7.11 (1H, s),7.17 (1H, s).

2-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]thiophene-4-carboxylicacid (Compound 19)

To a solution of 500 mg (1.24 retool) of2[-2-(E)-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-4-bromothiophenein 15 mL of tetrahydrofuran stirring under argon at -100 ° C. was added0.527 g (0.775 mL, 1.24 mmol, 1.6 M in hexanes) of n-BuLi. The reactionwas stirred for two minutes and purged with carbon dioxide for 20minutes. The reaction mixture was then allowed to warm to roomtemperature, acidified, and extracted using ether.

The ether extracts were washed with water, brine and dried (MgSO₄). Thesolvent was removed in-vacuo and the resulting residue taken-up inaqueous 2N sodium hydroxide and washed with ether. The resulting aqueouslayer was acidified using 1N HCl and extracted with ether. The etherlayer was washed with water and brine, and dried (MgSO₄). The solventwas removed in-vacuo and the resulting material purified by flashchromatography (10% ethyl acetate in hexanes) to give the title compoundas a white solid.

PMR (d⁶ -DMSO): 6 1.23 (12H, s), 1.62 (4H, s), 2.21 (3H, s), 2.23 (3H,s), 6.56 (1H, s), 7.07 (1H,s), 7.13 (1H, s), 7.45 (2H, s), 8.24 (2H, s).

(±-1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)ethanol

To a solution of 4.17 g (17.1 mmol) ofmethyl[3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen-2-yl] ketonein methanol at 0° C. was portionwise added 0.77 g (20.4 mmol) of sodiumborohydride and the resulting suspension stirred at 0° C. for 4 hours.Solvent was removed in-vacuo and the resulting solid taken-up in water,acidified using 1N HCl, and extracted three times with ether. The etherextracts were washed with water, brine and dried (MgSO₄). The solventwas removed in-vacuo and resulting residue purified using flashchromatography (SiO₂, 10% ethyl acetate in hexanes) to give a singleisomer: the title compound as a white solid.

PMR (CDCl₃): δ1.28 (12H, m), 1.47 (3H, d, J=6.5 Hz), 1.67 (4H, s), 2.49(3H, s), 5.08 (1H, m), 7.10 (1H, s), 7.45 (1H, s).

[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl]ethan-1-yl]triphenylphosphoniumbromide. (Compound 51)

To a solution of 3.87 g (15.7 mmol) of(±)-1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)ethanolin ether and hexanes at 0° C. under argon, was added 42.4 g (14.9 mL,157 mmol) of potassium bromide and the resulting mixture stirred for 2hours. Water was then dropwise added over a period of 30 minutes and thelayers separated. The aqueous layer was extracted three times withether. The ether layers were washed with water, brine, and dried(MgSO₄). The solvent was removed in-vacuo and the remaining residuetaken-up in benzene. Triphenylphosphine was added and the mixturestirred at room temperature for 24 hours. The mixture was thenconcentrated in-vacuo and the resulting solid recrystallized fromacetonitrile and ethyl acetate and hexanes to give the title compound asa white solid.

PMR (CDCl₃): 6 0.61 (3H, s), 0.89 (3H, s), 1.27 (6H, s), 1.62 (4H, m),1.85 (6H, d), 2.04 (3H, dd), 5.19 (2H, m), 6.62 (1H, d), 7.02 (1H, s),7.43 (6H, m), 7.68 (6H, m), 7.87 (3H, m).

2-[(E)-(2)-((5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-5-bromophiophene

To a solution of 3.00 g (5.26 mmol) of[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)ethan-1-yl]triphenylphosphoniumbromide in 60 mL of tetrahydrofuran at -78° C. under argon was dropwiseadded 2.24 g (3.29 mL, 5.26 mmol, 1.6 M in hexanes) of n-BuLi. Theresulting suspension was allowed to warm to room temperature where asolution of 1.01 g (0.63 mL, 5.26 mmol) of5-bromo-2-thiophenecarboxaldehyde in 10 mL of tetrahydrofuran wasdropwise added and the resulting mixture stirred for 20 hours at roomtemperature and then refluxed for 1 hour. The mixture was acidifiedusing 1N HCL, and extracted three times with ether. The ether extractswere washed with water, brine and dried (MgSO₄). The solvent was removedin-vacuo and resulting residue purified using flash chromatography(SiO₂, 2% ethyl acetate in hexanes) to give the title compound as awhite solid.

PMR (CDCl₃): δ1.28 (12H, s), 1.67 (4H, s), 2.24 (6H, 2×s), 6.45 (1H, s),6.75 (1H, d, J =3.9 Hz), 6.99 (1H, d, J =3.8 Hz), 7.07 (1H, s), 7.09(1H, s).

5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylicacid (Compound 21)

To a solution of 0.230 g (0.57 mmol) of2-[(E)-2-((5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-5-bromothiophenein ether was dropwise added 0.67 mL (1.14 mmol, 1.7 M in hexanes) oft-BuLi under argon at -78° C. The resulting mixture was stirred for 1.5hours, purged with carbon dioxide and allowed to warm to roomtemperature over a period of 16 hours. The mixture was acidified using1N HCl and extracted with ether. The ether layer was then washed withwater, brine, and dried (MgSO₄). Solvent was removed in-vacuo to give ablue solid which was recrystallized using ether in hexanes to give thetitle compound as a light blue solid.

PMR (d⁶ -DMSO): δ1.21 (12H, s), 1.60 (4H, s), 2.19 (3H, s), 2.24 (3H,s), 6.45 (1H, s), 6.61 (1H, s), 6.99 (1H, d, J=3.8 Hz), 7.06 (1H, s),7.12 (1H, s), 7.18 (1H, d, J=3.8 Hz), 7.67 (1H, d, J=3.8 Hz).

Ethyl5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylate(Compound 20)

A suspension of 0.161 g (0.437 mmol) of5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-thiophenecarboxylicacid, (Compound 21, 0.03 g, 0.655 mmol) in ETCH, 0.099 g (0.48 mmol) of1,3-dicyclohexylcarbodiimide, and 5.3 mg (0.044 mmol) of4-dimethylaminopyridine in 10 mL of methylene chloride was stirred atroom temperature for 16 hours. The reaction mixture was filtered and thefiltrate washed with water and brine. The organic layers were combinedand dried (MgSO₄), The solvent was removed in-vacuo and the residuepurified using flash chromatography (SiO₂, 5% ethyl acetate in hexanes)to give the title compound as a clear oil.

PMR (CDCl₃): δ1.27 (12H, s), 1.39 (3H, t, J=7.2 Hz), 1.68 (4H, s), 2.27(3H, s), 2.34 (3H, s), 4.37 (2H, q, J =7. Hz), 6.57 (1H, s), 7.00 (1H,d, J =3.8 Hz), 7.09 (1H, s), 7.11 (1H, s), 7.74 (1H, d, J =3.8 Hz).

Ethyl4-[(E)-2-(2,2,4,4,7-pentamethyl-chroman-6-yl)-propen-1-yl]-benzoate(Compound 24)

A mixture of 2.6 g (8.6 mmol) of ethyl[4-(diethoxyphosphinyl)methyl]benzoate (Compound 40) and 6.0 mL (8.6mmol) of potassium bis(trimethylsilyl)amide in tetrahydrofuran wasstirred for 30 minutes at room temperature under argon. A solution of1.0 g (4.3 mmol) of methyl (2,2,4,4,7-pentamethylchroman-6-yl) ketonealso known as 2,2,4,4,7-pentamethyl-6-acetylchroman (Compound 52) in THFwas added and the resulting mixture stirred for 20 hours. To this wasadded 4.3 mL (8.6 mmol) of 2M sodium ethoxide and the mixture stirred anadditional 2 hours. Sodium bicarbonate was then added and the mixtureextracted with ether. The ether layer was washed with brine and dried(MgSO₄). The solvent was removed in-vacuo and the resulting residuepurified using flash chromatography (SiO₂, 2% ethyl acetate in hexanes)to give a mixture of isomers which were separated using HPLC. (1% ethylacetate in hexanes) to give the title compound as a clear oil.

PMR (0.1% ethylbenzene in CDCl₃): δ1.37 (6H, s) , 1.38 (6H, s), 1.42(3H, t), 1.84 (4H, s), 2.21 (3H, s), 2.28 (3H, s), 4.41 (2H, q), 6.41(1H, s), 6.67 (1H, s), 7.10 (1H, s), 7.45 (2H, d, J-8.2 Hz), 8.06 (2H,d, J =8.2 Hz).

4-[(E)-2-(2,2,4,4,7-pentamethylchroman-6-yl) propen-1-yl]benzoic acid(Compound 25)

A solution of potassium hydroxide in ethanol was added to ethyl 4-[(E)-2- (2,2,4,4,7-pentamethylchroman-6-yl)propen-1-yl]benzoate (Compound24) and the resulting mixture stirred at room temperature. Solvent wasremoved in-vacuo and the resulting solid taken-up in water, acidifiedusing 1N HCl, and extracted three times was ether. The ether extractswere washed with water, brine and dried (MgSO₄). The solvent was removedin-vacuo to give the title compound as a pale yellow solid.

PMR (d⁶ -DMSO): δ1.38 (12H, s), 1.87 (2H, s), 2.23 (3H, s), 2.29 (3H,s), 6.44 (1H, s), 6.68 (1H, s), 7.10 (1H, s), 7.50 (2H, d, J=8.3 Hz),8.14 (2H, d, J =8.3 Hz).

Ethyl 4-[(E)-2-(2-methyl-5-tert-butylphenyl)propen-1-yl]benzoate(Compound 26)

A solution of 7.08 g (37 mmol) of 2-methyl-5-t-butylacetophenone(Compound 53 ) (obtained in accordance with the chemical literature) and10.42 g (37 mmol) of ethyl [4-(diethoxyphosphinyl)methyl]benzoate(Compound 40) in 30 mL of tetrahydrofuran was added via cannula into asuspension of 1.5 g (37 mmol) of sodium hydride in 30 mL oftetrahydrofuran at 0° C. under argon. The resulting suspension wasallowed to warm to room temperature and stirred for 72 hours. Theresulting sludge was taken-up in water and 1N HCl and extracted withether. The ether layers were washed with water, brine, and dried(MgSO₄). The solvent was removed in-vacuo and the residue purified usingflash chromatography (SiO₂, 1% ethyl acetate in hexanes) to give amixture of isomers which were separated using HPLC (0.5% ethyl acetatein hexanes) to give the title compound as a white solid.

PMR (CDCl₃): δ1.34 (9H, s), 1.41 (3H, t,) 1.69 (4H, s), 2.20 (3H, s),2.36 (3H, s), 4.38 (2H, q), 6.41 (1H, s), 7.04 (1H, m), 7.12 (1H, m),7.22 (1H, m), 7.42 (2H, d, J=8.3 Hz), 8.03 (2H, d, J=8.3 Hz).4-[(E)-2-(2-methyl-5-tert-butylphenyl)propen-1-yl]benzoic acid (Compound27)

A solution of potassium hydroxide in ethanol was added to 41 mg (0.12mmol) of ethyl 4-[(E)-2-2-methyl-5-tert-butylphenyl)propen-1-yl]benzoate(Compound 26) and the resulting mixture stirred at room temperature.Solvent was removed in-vacuo and the resulting solid taken-up in water,acidified using 1N HCl, and extracted with ether. The ether extractswere washed with water, brine and dried (MgSO₄). The solvent was removedin-vacuo to give the title compound as a yellow solid.

PMR (d⁶ -DMSO): δ1.24 (12H, s), 2.13 (3H, s), 2.28 (3H, s), 6.37 (1H,s), 7.09 (1H, d, J =8.0 Hz), 7.2 (2H, m), 7.49 (2H, d, J =8.3 Hz), 7.95(2H, d, J =8.3 Hz).

Methyl [3-chloro-5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone (Compound 54)

To a suspension Of 13 6 g (102 mmol) of aluminum chloride in 24 mL ofmethylene chloride at 0° C. under argon was added a solution of 7.98 g(7.23 mL, 102 mmol) of acetyl chloride, 18.88 g (84.8 mmol) of3-chloro-5,6,7,8-tetrahdro-3,5,5,8,8-pentamethylnaphthalen in 56 mL ofmethylene chloride. The resulting mixture was allowed to warm to roomtemperature over a period of three hours with stirring. The mixture wasrecooled to 0° C. and 1N HCl was added dropwise. The mixture was thentaken-up in water and extracted three times with methylene chloride. Theorganic layers were washed with 1N HCl, water, brine, and dried (MgSO₄)Solvent was removed in-vacuo and the resulting residue purified usingdistillation (116° C., 3 mm Hg) to give a mixture of starting materialand product.

PMR (CDCl₃): 6 1.27 (12H, s), 1.19 (4H, s), 2.65 (3H, s), 7.31 (1H, s),7.54 (1H, s). (±)-1-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanol

To a solution of 5.01 g (18.9 retool) of methyl[3-chloro-5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl] ketone(Compound 54) in methanol at 0° C. was portionwise added 1.0 g (26.4mmol) of sodium borohydride and the resulting suspension stirred at 0°C. for 2 hours. The mixture was then acidified using 1N HCl, andextracted three times with ether. The ether extracts were washed withwater, brine and dried (MgSO₄). The solvent was removed in-vacuo andresulting residue purified using flash chromatography (SiO₂, 5% ethylacetate in hexanes) to give the title compound as a white solid.

PMR (CDCl₃): δ1.26 (12H, m), 1.48 (3H, d, J =6.5 Hz), 1.67 (4H, s), 1.98(1H, s), 5.21 (1H, In), 7.23 (1H, s), 7.50 s).

[(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen,2-yl)ethan-1-yl]triphenylphosphoniumbromide (Compound 55)

To a solution of 3.15 g (11.8 mmol) of(±)-1-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetrainethylnaphthalen-2-yl)ethanolin ether and hexane stirring at 0° C. under argon, was added dropwise31.9 g (11.2 mL, 118 mmol) of phosphorus tribroinide and the mixturestirred 1.5 hours. Water was then carefully added and the mixtureextracted with several portions of ether. The ether extracts were washedwith water, sodium bicarbonate, brine, and dried (MgSO₄). The solventwas removed in-vacuo and the residual oil taken up in 175 mL of benzene.To this was added 3.09 g (11.8 mmol) of triphenylphosphine and thesolution stirred for 24 hours at room temperature. Purification was doneusing flash chromatography (SiO₂, 0.5% ethyl acetate in hexanes, 5% MeOHin methylene chloride) to give the title compound as a white foam.

PMR (CDCl₃): δ0.70 (3H, s), 1.02 (3H, s), 1.28 (12H, d, J =15 Hz), 1.62(4H, In), 2.01 (3H, dd, J=15, 9 Hz), 5.19 (1H, In), 6.79 (1H, s), 7.4-7.9 (16H, m).

Ethyl4-[(E)-2-(3-chloro-5,6,7,8-tetrahydro,5,5,8,8-tetramethylnaphthalen)-2-yl)propen-1-yl]benzoate(Compound 12)

A suspension of 0.91 g (1.54 mmol) of[(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetrainethylnaphthalen-2-yl)ethan-1-yl]triphenylphosphoniumbromide (Compound 55), 0.27 g 1.54 mmol) of freshly distilled4-carbethoxybenzaldehyde and 5.9 g (7.0 mL, 76.9 retool) of1,2-epoxybutane were combined under argon and refluxed for 96 hours. Theresulting dark brown solution was concentrated in-vacuo and the residuepurified using column chromatography (SiO₂, 2% ethyl acetate in hexanes)to give a mixture of isomers. Separation of isomers was achieved usingHPLC. (10% water in acetonitrile) to give the title compound as a whitesolid.

PMR (CDCl₃): δ1.29 (12H, s), 1.41 (3H, t, J=7.3 Hz), 1.69 (4H, s), 2.24(3H, s), 2.23 (3H, s), 4.49 (2H, q, J =6.8 Hz), 6.49 (1H, s), 7.20 (1H,s), 7.30 (1H, s), 7.48 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.4 Hz).

4[(E) -2-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoicacid (Compound 13)

A solution of potassium hydroxide in ethanol was added to 20 mg (0.049mmol) of ethyl4-[(E)-2-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl] benzoate (Compound 12) and the resulting mixture stirred atroom temperature for 24 hours. Solvent was removed in-vacuo and theresulting solid taken-up in water, acidified using 1N HCl, and extractedthree times with ether. The ether extracts were washed with water, brineand dried (MgSO₄). The solvent was removed in-vacuo and recrystallizedusing acetonitrile to give the title compound as a white solid.

PMR (CDCl₃): δ1.29 (12H, s), 1.70 (4H, s), 2.28 (3H, d, J=1.4 Hz), 6.51(1H, s), 7.20 (1H, s), 7.30 (1H, s), 7.51 (1H, d, J=8.4 Hz), 8.12 (1H,d, J=8.4 Hz).

Ethyl 4-[(E)-2-(2-methyl-4-tert-butylphenyl)propen-1-yl] benzoate(Compound 28)

A mixture of 3.17 g (10.5 mmol) of ethyl[4-(diethoxyphosphinyl)methyl]benzoate (Compound 40) and 7.6 mL (10.64mmol) of potassium bis(trimethylsilyl)amide (1.4 M in THF) was stirredfor 30 minutes. A solution of 1.0 g (5.3 retool) of2-methyl-4-t-butylacetophenone (Compound 56, obtainable in accordancewith the chemical literature) in 20 mL of dimethylsulfoxide was addedand the solution stirred for 20 hours. Sodium bicarbonate was added andthe solution extracted using ether. The ether extracts were washed withwater, brine and dried (MgSO₄). The solution was concentrated and theresidual oil purified using column chromatography (SiO₂, 3% ethylacetate in hexanes) to give a mixture of isomers. Photoisomerization (1hour, hexane, mercury lamp) increased the yield of trans isomer (45:55,E:Z). Isomers were separated using HPLC. (20% water in acetonitrile) togive the title compound as a clear oil.

4-[(E)-2-(2-methyl-4-tert-butylphenyl)propen-1-yl]benzoic acid (Compound29)

A solution of sodium hydroxide, 2-methoxyethanol and ether was added to70 mg (0.21 mmol) of ethyl4-[(E)-2-(2-methyl-4-tert-butylphenyl)propen-1-yl]benzoate (Compound 28)and the resulting mixture stirred at room temperature for 5 hours.Solvent was removed in-vacuo and the resulting solid taken-up in water,acidified using 1N HCl, and extracted with ether. The ether extractswere washed with water, brine and dried (MgSO₄). The solvent was removedin-vacuo to give the title compound as a yellow solid.

PMR (d⁶ -Acetone): 6 1.30 (9H, s), 2.19 (3H, d, J= 1.5 Hz), 2.33 (3H,s), 6.41 (1H, s), 7.12 (1H, d, J =8.0 Hz), 7.23 (2H, m), 7.54 (3.H, d, J=8.4 Hz), 8.05 (1H, d, J =8.4 Hz).

3-Bromo-5.6.7.8-tetrahydro-5.5,8,8-tetramethylnaphthalene

To a solution of 25 g (137 mmol) of 1,6-dichloro-1,6-dimethylhexane in28.9 mL (274 mmol) of bromobenzene was portionwise added 11.0 g (82.2mmol) of aluminum chloride at 0° C. under argon and the resultingsuspension stirred for 5 minutes at 0° C. and allowed to warm to roomtemperature for 15 minutes. 1N HCl was added dropwise. The mixture wastaken-up in water and extracted three times with ether. The ether layerswere washed with 1N HCl, sodium bicarbonate, brine, and dried (MgSO₄).Purification was done using distillation (110° C., 2 mm Hg) to give thetitle compound as a yellow solid.

PMR (CDCl₃): δ1.25 (6H, s), 1.27 (6H, s), 1.67 (4H, s), 7.16 (1H, d, J ⁼8.5 Hz), 7.23 (1H, dd, J =2.0, 8.5 Hz), 7.40 (1H, d, J=2.1 Hz).

Methyl [3,-bromo-5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl!ketone (Compound 57)

To a suspension of 6.16 g (46.3 mmol) of aluminum chloride in methylenechloride at 0° C. under argon was added a solution of 3.29 mL(den=1.104, 46.3 mmol) of acetyl chloride, 10.3 g (38.5 mmol) of3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in methylenechloride. The resulting mixture was stirred for 2 hours and allowed towarm to room temperature over a period of 16 hours. The mixture wasrecooled to 0° C. and 1N HCl was added dropwise. The mixture was thentaken-up in water and extracted three times with methylene chloride. Theorganic layers were washed with 1N HCl, water, brine, and dried (MgSO₄).Solvent was removed in-vacuo and the resulting residue purified usingdistillation (116° C., 3 mm Hg) to give a mixture of starting materialand product.

PMR (CDCl₃): δ1.27 (12H, s), 1.68 (4H, s), 2.64 (3H, s), 7.45 (1H, s),7.50 (1H, s). Ethyl 4-[(E) -2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoate(Compound 14)

A mixture of 5.56 g (18.7 mmol) of ethyl[4-(diethoxyphosphinyl)methyl]benzoate (Compound 40) and 74 mL (18.7mmol) of potassium bis(trimethylsilyl)amide was stirred for 38 minutes.A solution of 2.0 g (6.5 mmol) of methyl[3-bromo-5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone(Compound 57) in 30 mL of dimethylsulfoxide was added and the solutionstirred for 64 hours. Sodium bicarbonate was added and the solutionextracted using methylene chloride and dried (MgSO₄). Solvent wasremoved in-vacuo and the residual oil purified using flashchromatography (SiO₂, 3% ethyl acetate in hexanes).

PMR (CDCl₃): δ1.27 (12H, s), 1.41 (3H, t), 1.68 (4H, s), 2.24 (3H, s),4.38 (2H, q), 6.45 (1H, s), 7.18 (1H, s), 7.47 (3H, m), 8.04 (1H, s),8.08 (1H, s).

4[(E)-2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoic acid (Compound 15)

A solution of sodium hydroxide, 2-methoxyethanol and ether was added to50 mg (0.11 mmol) of ethyl4-[(E)-2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtha-len-2-yl)propen-1-yl]benzoate(Compound 14) and the resulting mixture stirred at room temperature for17 hours. Solvent was removed in-vacuo and the resulting solid taken-upin water, acidified using 2N HCl, and extracted with ether. The etherextracts were washed with water, brine and dried (MgSO₄). The solventwas removed in-vacuo to give the title compound as a white solid.

PMR (d⁶ -DMSO): δ1.30 (12H, s), 1.69 (4H, s), 2.26 (3H, d, J =1.3 Hz),6.48 (1H, s), 7.20 (1H, s), 7.49 (1H, s), 8.14 (2H, d, J =8.3 Hz).

Methyl [3-ethyl-5,5,8,8-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone (Compound 58)

To a suspension of 4.59 g (34.4 mmol) of aluminum chloride in 20 mL ofmethylene chloride at -5° C. under argon was added a solution of 2.32 g(2.10 mL, 29.5 mmol) of acetyl chloride and 4.95 g (23 mmol) of3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (obtainable inaccordance with U.S. Pat. No. 2,897,237, the specification of which isexpressly incorporated by reference) in 10 mL of methylene chloride overa period of I hour. The resulting mixture was stirred at -10 to +5° C.for 3 hours. The mixture was then taken-up in water and extracted threetimes with methylene chloride. The organic layers were washed with brineand dried (MgSO₄). Solvent was removed in-vacuo and the resultingresidue purified using flash chromatography (SiO₂, 10% ethyl acetate inhexanes) to give the title compound as a white solid.

PMR (CDCl₃): δ1.20 (3H, t, J=7.5 Hz), 1.29 (6H, s), 1.30 (6H, s), 1.69(4H, s), 2.57 (3H, s), 2.84 (2H, q, J=7.3 Hz), 7.17 (1H, s), 7.59 (1H,s).

Methyl[3-isopropyl-5,5,8,8,-tetramethyl(5,6,7,8-tetrahydronaphthalen)-2-yl]ketone(Compound 59)

To a suspension of 5.80 g (43.5 mmol) of aluminum chloride in 15 mL ofmethylene chloride at -5° C. under argon was added a solution of 3.20 g(2.90 mL, 41 mmol) of acetyl chloride and 6.58 g (29 mmol) of3-isopropyl-5,5,8,8-tetraamethyl-5,6,7,8-tetrahydronaphthalene(obtainable in accordance with U.S. Pat. No. 2,879,237, thespecification of which is expressly incorporated by reference) in 25 mLof methylene chloride over a period of 1 hour. The resulting mixture wasstirred at -5° C. for 2.5 hours. The mixture was then cooled to 0° C.,taken-up in water and extracted three times with hexane. The organiclayers were washed with brine and dried (MgSO₄). Solvent was removedin-vacuo and the resulting residue purified using flash chromatography(SiO₂, 5% ethyl acetate in hexanes) to give the title compound as awhite solid.

PMR (CDCl₃): δ1.22 (6H, s), 1.24 (6H, s), 1.29 (6, s), 1.69 (4H, s),2.49 (3H, s), 2.56 (3H, s), 3.50 (1H, pentet, J =6.8 Hz ), 7.32 (1H, s), 7.46 (1H, s).

Ethyl 5- [(E)]-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-furancarboxylate(Compound 22)

A mixture of sodiumhydride in 10 mL of dimethylsulfoxide was heated at55° C. for 1 hour and added to 1.159 g (4.00 mmol) ofethyl-2-[5-(diethoxyphosphinyl)methyl]furanoate (Compound 42). Theresulting deep red solution was stirred 45 minutes at room temperatureand added to a solution of 0.501 g (2.05 mmol) of methyl[3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen)-2-yl] ketone(Compound 50) and the resulting solution stirred at room temperature for48 hours. Sodium bicarbonate was added and the solution extracted usingether and dried (MgSO₄). The solution was concentrated and the residualoil purified using column chromatography (SiC₂, 5% ethyl acetate inhexanes). Separation of isomers was achieved using HPLC.

Ethyl5-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-3-nicotinoate(Compound 16)

To 0.21 g (0.70 mmol) of ethyl3-5-(diethoxyphosphinyl)methyl]nicotinoate (Compound 43) stirring at 0°C. under argon was dropwise added 0.90 g (1.0 ml, 1 mmol) of sodiumbis(trimethylsilyl)amide (1M in tetrahydrofuran). The resulting deep redsolution was stirred 1 hour at room temperature and added to a solutionof 0.154 g (0.63 mmol) of methyl[3,5,5,8,8-pentamethyl(5,6,7,8-tetrahydronaphthalen)-2-yl] ketone(Compound 50) and the resulting solution stirred at room temperature for72 hours. Sodium bicarbonate was added and the solution extracted usingether and dried (MgSO₄). The solution was concentrated and the residualoil purified using column chromatography (SiO₂, 5% ethyl acetate inhexanes). Separation of isomers was achieved using HPLC.

What is claimed is:
 1. A compound of the formula ##STR18## where R₁ islower alkyl, Cl, Br, or I;R₂ is H, lower alkyl, Cl, Br, or I; R₃ islower alkyl, Cl, Br, I, OR11, SR₁₁, OCOR₁₁, SCOR11, NH₂, NHR₁₁, N(R₁₁)₂,NHCOR₁₁, or NR₁₁ --COR₁₁ ; R₅ and R₆ independently are H, lower alkyl,Cl, Br, I, lower alkoxy or lower thioalkoxy of 1 to 6 carbons; A is(CH₂)_(n) where n is 0-5, lower branched chain alkyl having 3 to 6carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbonsand 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triplebonds; B is COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR9R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O,--COR₇, CR₇ (OR₁₂)₂, or CR₇ OR₁₃ O, where R₇ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl orlower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl groupof 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenylor lower alkylphenyl, R₁₁ is alkyl of 1 to 10 carbons, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons; R₂₀ is independently H or lower alkyl, and Y₁ is thienyl,furyl or pyridyl.
 2. A compound of claim 1 wherein R₂₀ is methyl.
 3. Acompound of claim 1 wherein R₂, R₅ and R₆ are hydrogen.
 4. A compound ofclaim 1 wherein R₁ is methyl.
 5. A compound of claim 1 wherein R₃ ismethyl, Cl or Br.
 6. A compound of claim 1 wherein A is (CH₂)_(n), n=0and B is COOH or COOR₈.
 7. A compound of claim 6 wherein Y₁ is thienyl,R₁, R₃ and R₂₀ are methyl, R₂, R₅ and R₆ are hydrogen and A is(CH₂)_(n), n=0 and B is COOH or COOR₈.
 8. A compound of claim 6 whereinY₁ is furyl, R₁, R₃ and R₂₀ are methyl, R₂, R₅ and R₆ are hydrogen and Ais (CH₂)_(n), n=0 and B is COOH or COOC₂ H₅.
 9. A compound of claim 6wherein Y₁ is pyridyl, R₁, R₃ and R₂₀ are methyl, R₂, R₅ and R₆ arehydrogen and A is (CH₂)_(n), n=0 and B is COOH or COOC₂ H₅.